New pharmaceutical compositions of flurbiprofen and glucosamin

ABSTRACT

The present invention relates to new pharmaceutical compositions of flurbiprofen or a pharmaceutically acceptable salt thereof and glucosamine or salts thereof. Particularly, the present invention relates to new pharmaceutical compositions for use in the treatment of pain and inflammatory symptoms associated with joint and cartilage disorders, especially with osteoarthritis and rheumatoid arthritis.

FIELD OF INVENTION

The present invention relates to new pharmaceutical compositions offlurbiprofen or a pharmaceutically acceptable salt thereof andglucosamine or salts thereof. Particularly, the present inventionrelates to new pharmaceutical compositions for use in the treatment ofpain and inflammatory symptoms associated with joint and cartilagedisorders, especially with osteoarthritis and rheumatoid arthritis.

BACKGROUND OF INVENTION

Joint and cartilage disorders, is a painful degenerative condition thatresults in the deterioration of cartilage tissues that support theweight-bearing joints in the body. Once the cartilage is thinned orlost, the constant grinding of bones against each other causes pain andstiffness around the joint. Abnormal and excess bone formations calledspurs grow from the damaged bones, causing further pain and stiffness.It is believed that degenerative joint disorders affect 80% of peopleover the age of 60. Degenerative joint disorders include, for example,osteoarthritis, rheumatoid arthritis, other rheumatic disorders withcartilage breakdown, chondrolysis after joint trauma, for example, aftermeniscus or patella injuries or torn ligaments, or chondrolysisassociated with prolonged immobilization of joints.

Osteoarthritis is the most prevalent form of arthritis which is apainful, degenerative joint disease that often involves the hips, knees,neck, lower back, or the small joints of the hands. It is characterizedby pain and progressive degeneration of cartilage in synovial joints andvertebrae, leading to significant reduction of mobility and quality oflife. Osteoarthritis usually develops in joints that are injured byrepeated overuse in the performance of a particular job or a favoritesport or from carrying around excess body weight. Eventually this injuryor repeated impact thins or wears away the cartilage that cushions theends of the bones in the joint so that the bones rub together, causing agrating sensation. Joint flexibility is reduced, bony spurs develop, andthe joint swells. Usually, the first symptom a person has withosteoarthritis is pain that worsens following exercise or immobility.

Rheumatoid arthritis is an autoimmune inflammatory disease in which thebody releases enzymes that attack its own healthy tissues. In rheumatoidarthritis, these enzymes destroy the linings of joints causing pain,swelling, stiffness, deformity, and reduced movement and function.Rheumatoid arthritis also may include systemic symptoms.

Hence, pharmacological treatment of arthritis involves two therapeuticgoals:

-   -   Analgesic & anti-inflammatory treatment: Relief from pain and        inflammation of the soft tissue surrounding the joint.    -   Disease-modifying treatment to treat the underlying pathology.

Flurbiprofen is a well known, propionic acid derivative, also known asNSAID (non-steroidal anti-inflammatory drug), with the analgesic andanti-inflammatory activities it possesses. It is used in muscle-skeletaland joint disorders such as ankylosing spondylitis, osteoarthritis andrheumatoid arthritis, in soft-tissue disorders such as sprains andstrains and for postoperative pains and mild to moderate pain includingdysmenorrhoea and migraine. Its chemical structure is illustrated withFormula I given below.

Flurbiprofen is mostly administrated orally in dosages about 150 to 200mg, may also be increased to 300 mg daily in acute or severe conditionsif necessary.

One disadvantage of the oral administration of compositions comprisingflurbiprifen, is that the patient is likely to experience unpleasantside effects, including gastrointestinal (GI) adverse effects includinginflammation, spontaneous gastric bleeding, ulceration and perforationof the stomach, which can be life threatening. Thus, using flurbiprofenin high dosages may increase the GI adverse effects.

There are various patent applications in prior art in relation toflurbiprofen compositions, for example, U.S. Pat. No. 3,755,427describes the flurbiprofen molecule and the anti-inflammatory,analgesic, antipyretic and anti-toxic effects of flurbiprofen.

The document U.S. Pat. No. 4,014,993 discloses the use of flurbiprofenin platelet aggregation. The document EP137668 discloses the use offlurbiprofen in the treatment of alveolar bone resorption.

Glucosamine is an amino sugar and aprominent precursor in thebiochemical synthesis of glycosylated proteins and lipids. Glucosamineis part of the structure of the polysaccharides chitosan and chitin andit is naturally present in the shells of shellfish, animal bones andbone marrow. It is also present in some fungi and can be alsosynthetically derived. Glucosamine is used for the treatment ofosteoarthritis. Glucosamine may be administered in dosages about 500 to2500 mg per day.

There are various patent applications in prior art in relation toglucosamine compositions but none of them are specifically used incombination with flurbiprofen in oral administration as tablet orcapsule dosage form.

For example, U.S. 2008/0227747 A1 discloses a therapeutic compositionand methods for the treatment and prevention of a degenerative jointdisorder and/or cardiovascular disease comprising polycosanols,glucosamine and chondroitin. Composition further may comprise NSAIDs,but neither an example nor flurbiprofen as one of the NSAIDs isdisclosed in the patent application in combination with glucosamine.

It is well known that drugs used in the same therapeutic area or evenfor treating the same indication cannot always be combined a priori withthe expectation of at least additive therapeutic effects. The scientificliterature is full of examples wherein compounds of different classes,which are used to treat the same indications, cannot be combined intosafe and efficacious dosage forms thereby resulting in incompatible drugcombinations. The reasons for this unexpected lack of compatibility arevaried; however, it is often found that the incompatible drugcombinations result in increased side effects, unwanted druginteractions or new side effects.

However, not all combinations of NSAIDs and glucosamine are suitable, interms of safety or efficacy, than the administration of a singleproduct. Thus, no orally-administrable pharmaceutical composition hasbeen produced until today, which contains a combination of flurbiprofenand glucosamine. Even if some medicaments comprising either of theseactive agents have been administered concomitantly in practice, thisfact requires the patients to carry more than one drug and causesapplication-related difficulties. Additionally, administering andformulating a combination, in place of the individual use of each activeagent, may provide improved treatment features.

Another problem is related to combine these two active ingredients inone dosage form such as tablet or capsule, it would require a dosageform having approximately or more than 1000 mg active ingredients intotal without any further tablet or capsule excipients. This is anamount that would create a very large tablet or capsule size that wouldnot be swallowable, or it would require composition that would requireingesting multiple tablets to achieve the desired effect.

Accordingly, based on said drawbacks, a novelty is required in the artof pharmaceutical compositions having therapeutic effects against painand inflammatory symptoms associated with joint and cartilage disorders,especially with osteoarthritis and rheumatoid arthritis.

Therefore, the object of the present invention is to provide newpharmaceutical compositions comprising flurbiprofen and glucosamin foruse in the treatment of pain and inflammatory symptoms associated withjoint and cartilage disorders, especially with osteoarthritis andrheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION

The main object of the present invention is to treat, reduce, or preventthe degenerative joint and cartilage disorders by administering to asubject in need thereof a therapeutically effective amount of acomposition comprising flurbiprofen and glucosamine, for oraladministration, which overcomes the above described problems in priorart and have additional advantages over them.

A further object of the invention is to eliminate the GI adverse effectsof flurbiprofen when it is administered orally in high terapeuticeffective amounts for a long time. It is known that the treatment of thedegenerative joint and cartilage disorders, especially osteoarthritisand rheumatoid arthritis needs a long treatment period. Therefore to useof flurbiprofen for a long time with high terapeutic effective amountsmay increase the possibility of GI adverse effects of flurbiprofen. As arule, after a long-term administration of a drug, drug addictiondevelops and as a consequence its dosage should be increased. Thiscertainly affects the occurrence of side effects.

The present invention provides the solution to this problem by using notmore than 15% flurbiprofen by combining it with glucosamin not less than45% by weight. It has been found surprisingly that this ratios have anincreased/synergistic effect over the flurbiprofen's analgesic andantiinflammatory activity even with low doses.

The role which glucosamine sulfate plays in the treatment or preventionof the degenerative joint and cartilage disorders is most likelyassociated directly its ability to act as the most important substratefor glycosaminoglycans and a basis of hyaluronic acid. A successfultreatment of osteoarthritis and rheumatoid arthritis must control paineffectively as well as slow down or ensure the reverse development ofjoint degeneration process. It has been found that the introduction ofglucosamone sulfate in a quantity of not less than 45% of the totalweight of the composition makes it possible to ensure achondroprotective and anti-inflammatory effect of the composition andprevents destructive effect of glucocorticoids on chondrocytes and toreduce a need for NSAID (i.e. flurbiprofen) in high dosage for patientssuffering from osteoarthritis and rheumatoid arthritis which in turnmakes it possible to decrease side effect risks.

Accordingly, when flurbiprofen is used for a long period of time, it mayhave a desensitising effect. It has been also found that whenflurbiprofen is used in an amount of not more than 15% by combinationwith glucosamine not less than 45% of the total weight of thecomposition makes it possible to ensure increased analgesic andanti-inflammatory effect of the composition, whilst reducing the painand inflammation syndrome in degenerative joint and cartilage disorderssynergisticly. Thus this also reduces the risk of the GI side effects.In one embodiment flurbiprpfen amount is present not more than 10% byweight and glucosamine sulfate amount is present not less than 50% byweight of the total composition.

This ratios also ensure the required effective doses for the therapywithout the need of taking the medicine three times a day. In prior art,the formulations comprising glucosamine are taken three times a day. Dueto increased tablet weight when trying to increase the requiredglucosamine effective doses (i.e 750 mg to 1000 mg/tablet or capsule)which should be the minimum 500 mg, occurs some problems during themanufacturing of the composition itself, and for the patient compliancetoo. Because it would require a dosage form having approximately or morethan 1000 mg active ingredients in total without any further tablet orcapsule excipients. This is an amount that would create a very largetablet or capsule size that would not be swallowable, or it wouldrequire composition that would require ingesting multiple tablets toachieve the desired effect which can be difficult for the patients.

Therefore it has been found that in certain ratios of flurbiprofen toglucosamine which is in the range of 0.010 to 10.0, preferably 0.10 to5.0, and more preferably 0.10 to 2.0 helps the composition easilyprocessed into a tablet or capsule dosage form, in desired weight whichcan easily be swallowed by the patients, whilst maintaining orincreasing the therapeutic effective doses for the treamnet of joint andcartilage disorders.

According to a preferred embodiment of the present invention, saidnovelty is realized with the composition comprising, flurbiprofen orpharmaceutically acceptable salts thereof and glucosamine orpharmaceutically acceptable salts thereof.

Flurbiprofen useful in accordance with this invention comprises thepharmaceutically acceptable salts and esters of flurbiprofen, andfurther includes the conventionally used racemic mixture which comprisesthe S- and R-enantiomers of flurbiprofen. In a preferred embodiment ofthe present invention, flurbiprofen is in an amount of 5.0 to 15.0% byweight of the total tablet, preferably it is 5.0 to 10.0% by weight ofthe total tablet.

The preferred salts of glucosamine in accordance with this inventioncomprise N-acetyl-glucosamine, glucosamine hydrochloride and glucosaminesulfate and mixtures thereof. In a preferred embodiment of the presentinvention, the salt is sulfate salt. Glucosamine sulfate . thereof is inan amount of 45.0 to 70.0% by weight of the total tablet, preferably itis 50.0 to 70.0% by weight of the total tablet, more preferably it is60.0% to 70.0% by weight of the total tablet.

According to a preferred embodiment the pharmaceutical composition ofthe present invention, therapeutic effective amount of flurbiprofen ispresent between 100-500 mg/day and therapeutic effective amount ofglucosamine sulfate is present between 500-2000 mg/day. In one aspect,flurbiprofen is present in an amount of between 100-300 mg/day andglucosamine sulfate is present in an amount 500-1500 mg/day.

Another preferred embodiment of the present invention comprises at leastone or more excipient. According to a preferred embodiment of thepresent invention, said excipient comprise at least one or morediluents, disintegrants, glidants, lubricants, binders, coloring agents,flavouring agents.

In a preferred embodiment of the present invention, suitable diluents isselected from a group comprising lactose monohydrate, microcrystallinecellulose, corn starch, pregelatinized starch, mannitol, calciumphosphate anhydrate, calcium phosphate dihydrate, calcium phosphatetrihydrate, dibasic calcium phosphate, calcium carbonate, calciumsulfate, carboxymethyl cellulose calcium, powdered cellulose, celluloseacetate or mixtures thereof.

In a preferred embodiment of the present invention, suitabledisintegrant is selected from a group comprising croscarmellose sodium,hydroxypropyl cellulose, xylitol, crospovidone, low-substitutedhydroxypropyl cellulose (L-HPC) and sodium starch glycolate, corn starchor mixtures thereof. In one aspect, disintegrant is present in an amountof from 5.0 to 25.0% by weight of the total tablet composition.

In a preferred embodiment of the present invention, suitable glidant iscolloidal silicon dioxide or talc. In one aspect, glidant is present inan amount of from 0.10 to 5.0% by weight of the total tabletcomposition.

In a preferred embodiment of the present invention, suitable lubricantis selected from the group comprising magnesium stearate, sodium stearylfumarate, polyethylene glycol, stearic acid, metal stearates, boricacid, sodium chloride benzoate and acetate, sodium or magnesium laurylsulfate or mixtures thereof. In one aspect, lubricant is present in anamount of from 0.10 to 5.0% by weight of the total tablet composition.

In a preferred embodiment of the present invention, suitable binder isselected from a group comprising polymethacrylate, glyceryl behenate,polyvinylpyrrolidone (povidone), hydroxypropyl methyl cellulose (HPMC),hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose(Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and othercellulose derivatives, polyethylene oxide, gelatin, starch, xanthan gum,guar gum, alginate, carrageen, pectin, carbomer, cellulose acetatephthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose,polaxomer, polyethylene glycol (PEG) or mixtures thereof. In one aspect,binder is used optionally and may present in an amount of from 0.10 to10.0% by weight of the total tablet composition.

In a preferred embodiment of the present invention, suitable coloringagent is selected from a group comprising iron oxides (such as; ironoxide yellow, red or black), Food, Drug & Cosmetic (FD&C) dyes, poncau,indigo blue, indigotine blue, carmoisine indigotine, quinoline yellow,flaming red, carmine, carmoisine, sunset yellow or mixtures thereof. Inone aspect, coloring agent is used optionally and may present in anamount of from 0.01 to 1.00% by weight of the total tablet composition.

In a preferred embodiment of the present invention, suitable flavouringagent is selected from a group comprising fruit flavours such as orange,banana, strawberry, cherry, wild cherry, lemon; and other flavours suchas cardamom, anise, peppermint, menthol, vanillin and ethyl vanillin ormixtures thereof. In one aspect, flavouring agent is used optionally andmay present in an amount of from 0.1 to 2.0 by weight of totalcomposition.

In a preferred embodiment according to the present invention, saidpharmaceutical composition ccomprises,

-   -   a. flurbiprofen at 5.0-15.0% by weight,    -   b. glucosmain sulfate at 45.0-70.0% by weight,    -   c. lactose monohydrate at 10.0-20% by weight,    -   d. microcrystalline cellulose at 5.0-10% by weight,    -   e. croscarmellose sodium at 1.0-5.0% by weight,    -   f. hydroxypropyl cellulose at 1.0-5.0% by weight,    -   g. colloidal silicon dioxide at 0.10-2.0% by weight,    -   h. magnesium stearate at 0.10-2.0% by weight,

In another preferred embodiment according to the present invention, saidpharmaceutical composition comprises,

-   -   a. flurbiprofen at 5.0-10.0% by weight,    -   b. glucosmain sulfate at 50.0-70.0% by weight,    -   c. lactose monohydrate at 10.0-20% by weight,    -   d. microcrystalline cellulose at 5.0-10% by weight,    -   e. croscarmellose sodium at 1.0-3.0% by weight,    -   f. hydroxypropyl cellulose at 1.0-3.0% by weight,    -   g. colloidal silicon dioxide at 0.10-1.0% by weight,    -   h. magnesium stearate at 0.10-1.0% by weight,

According to another preferred embodiment of the present invention, theflurbiprofen or a pharmaceutically acceptable salts thereof combinationscomprising glucosamine is used in the treatment of pain and inflammatorysymptoms associated with joint and cartilage disorders, especially withosteoarthritis and rheumatoid arthritis.

According to a further embodiment of the present invention, flurbiprofenand glucosamine sulfate may further be combined with chondroitinsulfate. The therapeutic effective amount of chondroitin sulfate ispresent between 500-1500 mg/day.

According to this embodiment of the present invention, saidpharmaceutical composition comprises,

-   -   a. flurbiprofen at 5.0-15.0% by weight,    -   b. glucosmain sulfate at 45.0-70.0% by weight,    -   c. chondroitin sulfate at 25-50% by weight,    -   d. lactose monohydrate at 5.0-20% by weight,    -   e. microcrystalline cellulose at 1.0-10% by weight,    -   f. croscarmellose sodium at 1.0-5.0% by weight,    -   g. hydroxypropyl cellulose at 1.0-5.0% by weight,    -   h. colloidal silicon dioxide at 0.10-2.0% by weight,    -   i. magnesium stearate at 0.10-2.0% by weight,

According to a further embodiment of the present invention, flurbiprofenand glucosamine sulfate may further be combined withmethylsulfonylmethane or flurbiprofen, glucosamine sulfate andchondroitin sulfate may further be combined with methylsulfonylmethane.The therapeutic effective amount of methylsulfonylmethane is presentbetween 400-1200 mg/day.

According to a further embodiment of the present invention, flurbiprofenand glucosamine sulfate may further be combined with capsaicin orflurbiprofen, glucosamine sulfate and chondroitin sulfate may further becombined with capsaicin.

According to another embodiment of the invention, the pharmaceuticalcomposition is in the form of a tablet or capsule, it may optionally inthe form of a bilayer tablet.

According to another preferred embodiment of the present invention, theformulation is orally administered as twice-a-day dosage regimen whichincreases the patient compliance according to the dosage regimen taken 3times a day. Thus, patient doesn't need to carry out the tablet orcapsule with himself also to prevent the forgotten an omitted doseduring the day. Therefore, it is very convenient to take the medicineonce in the morning and the second in the evening.

As a further embodiment of the invention, it is possible to preparetablets or granules by direct compression. Likewise the dry and wetgranulation processes are possible as well.

The preferred direct compression process of the present invention forpreparing the pharmaceutical composition comprises the following steps;

-   -   a. blending flurbiprofen, glucosamine sulphate, microcrystalline        cellulose, lactose monohydrate, crosscarmellose sodium and        hydroxypropylcellulose progressively, wherein the blending time        is preferably 20 min.,    -   b. adding magnesium stearate and colloidal silicon dioxide to        the powder mixture above and blending progressively for about 5        min.    -   c. compressing the final powder mixture to form tablets, or        filling into capsules,    -   d. optionally coating the tablets.

The preferred dry granulation process of the present invention forpreparing the pharmaceutical composition comprises the following steps;

-   -   a. mixing flurbiprofen and glucosamine sulfate with lactose        monohydrtate, ½ of microcrystalline cellulose, crosscarmellose        sodium and hydroxypropylcellulose and granulating the mixture        progressively,    -   b. compacting the blended mixture,    -   c. adding rest of the microcrystalline cellulose, colloidal        silicon dioxide and magnesium stearate to this mixture of step        b., and further progressive blending until obtaining a        homogenous powder mixture,    -   d. compressing the blended mixture to form tablets or filling        into capsules,    -   e. optionally coating the tablets.

The preffered wet granulation process for preparing the pharmaceuticalcomposition comprising the following steps;

-   -   a. mixing flurbiprofen and glucosamine sulfate with lactose        monohydrtate, microcrystalline cellulose, ½ of crosscarmellose        sodium and hydroxypropylcellulose and blending,    -   b. adding water or water+alcohol mixture to this mixture and        blending to form granules,    -   c. sieving and drying the wet granules in oven or fluid bed        dryer and sieving the dry granules,    -   d. rest of the crosscarmellose sodium, colloidal silicon dioxide        and magnesium stearate are mixed with the dry granule mixture,    -   e. compressing the blended mixture to form tablets, or filling        into capsules,    -   f. optionally coating said tablets.

This invention is further defined by reference to the followingexamples. Although the example is not intended to limit the scope of thepresent invention, it should be considered in the light of thedescription detailed above.

Example 1 Capsul or Tablet

Ingredients % amount flurbiprofen 8.70 glucosamin sulfate 65.20 lactosemonohydrate 15.60 microcrystalline cellulose 7.00 croscarmellose sodium1.30 hydroxypropyl cellulose 1.50 colloidal silicon dioxide 0.36magnesium stearate 0.30

The process of the composition is carried out with one of the processesas given above in detail.

Example 2 Capsul or Tablet

Ingredients % amount flurbiprofen 8.00 glucosamin sulfate 45.0chondroitin sulfate 30.0 lactose monohydrate 10.50 microcrystallinecellulose 3.50 croscarmellose sodium 1.20 hydroxypropyl cellulose 1.30colloidal silicon dioxide 0.30 magnesium stearate 0.20

The process of the composition is carried out with one of the processesas given above in detail.

1. A pharmaceutical composition for oral administration, comprising flurbiprofen or one or more pharmaceutically acceptable salts thereof and glucosamine or one or more pharmaceutically acceptable salts thereof.
 2. The pharmaceutical composition according to claim 1, wherein the one or more pharmaceutically acceptable salts of glucosamine comprises N-acetyl, hydrochloride, sulfate or mixtures thereof, preferably the salt is sulfate salt.
 3. The pharmaceutical composition according to claim 1, wherein the amount of flurbiprofen or pharmaceutically acceptable salts thereof is not more than 15% by weight.
 4. The pharmaceutical composition according to claim 1, wherein the amount of glucosamine or the one or more pharmaceutically acceptable salts thereof is between 45% and 70% by weight of the total composition.
 5. The pharmaceutical composition according to claim 1, wherein the amount of flurbiprofen to glucosamine is in the range of 0.010 to 10.0, preferably 0.10 to 5.0, and more preferably 0.10 to 2.0.
 6. The pharmaceutical composition according to claim 1, wherein flurbiprofen is present in an amount of between 100-500 mg/day and glucosamine sulfate is present in an amount of 500-2000 mg/day.
 7. The pharmaceutical composition according to claim 1, further comprising at least one or more pharmaceutically acceptable excipients.
 8. The pharmaceutical composition according to claim 7 wherein said one or more pharmaceutically acceptable excipients comprise at least one or more diluents, disintegrants, glidants, lubricants, binders, coloring agents, or flavouring agents.
 9. The pharmaceutical composition according to claim 8, wherein said one or more dliuents are selected from lactose monohydrate, microcrystalline cellulose, corn starch, pregelatinized starch, mannitol, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, dibasic calcium phosphate, calcium carbonate, calcium sulfate, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate and mixtures thereof
 10. The pharmaceutical composition according to claim 8, wherein said one or more disintegrants are selected from croscarmellose sodium, hydroxypropyl cellulose, xylitol, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, corn starch and mixtures thereof
 11. The pharmaceutical composition according to claim 8, wherein said one or more glidants is colloidal silicon dioxide or talc.
 12. The pharmaceutical composition according to claim 8, wherein said one or more lubricants are selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, stearic acid, metal stearates, boric acid, sodium chloride benzoate and acetate, sodium or magnesium lauryl sulfate and mixtures thereof.
 13. The pharmaceutical composition according to claim 1, comprising, a. flurbiprofen at 5.0-15.0% by weight, b. glucosmain sulfate at 45.0-70.0% by weight, c. lactose monohydrate at 10.0-20% by weight, d. microcrystalline cellulose at 5.0-10% by weight, e. croscarmellose sodium at 1.0-5.0% by weight, f. hydroxypropyl cellulose at 1.0-5.0% by weight, g. colloidal silicon dioxide at 0.10-2.0% by weight, and h. magnesium stearate at 0.10-2.0% by weight.
 14. The pharmaceutical composition according to claim 1, further comprising chondroitin sulfate.
 15. The pharmaceutical composition according to claim 14, comprising, a. flurbiprofen at 5.0-15.0% by weight, b. glucosmain sulfate at 45.0-70.0% by weight, c. chondroitin sulfate at 25-50% by weight, d. lactose monohydrate at 5.0-20% by weight, e. microcrystalline cellulose at 1.0-10% by weight, f. croscarmellose sodium at 1.0-5.0% by weight, g. hydroxypropyl cellulose at 1.0-5.0% by weight, h. colloidal silicon dioxide at 0.10-2.0% by weight, and i. magnesium stearate at 0.10-2.0% by weight.
 16. The pharmaceutical composition according to claim 1, further comprising methylsulfonylmethane.
 17. The pharmaceutical composition according to claim 1, further comprising capsaicin.
 18. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a tablet or capsule.
 19. The pharmaceutical composition according to claim 18, wherein the composition is in the form of a bilayer tablet.
 20. (canceled)
 21. A method for the treatment of pain and inflammatory symptoms associated with joint and cartilage disorders in a patient, comprising administering an effective amount of the pharmaceutical composition of claim 1 to the patient in need thereof. 